Collaborator @amelierocks.bsky.social complemented this with predictions of protein stability and conservation scores. In combination with functional work this establishes a framework for classifying suspected disease variants, which we hope will aid assessment of NALCN variant pathogenicity

@chowhanchua.bsky.social implemented use of a combination of multiple parameters derived from two-electrode voltage-clamp electrophysiology recordings. These allow us to classify LoF and GoF phenotypes and to provide mechanistic insight into the molecular mechanism underlying specific variants.

De novo and inherited NALCN variants can lead to severe developmental syndromes. Although variants of uncertain significance or presumed pathogenic variants have been studied in heterologous systems before, there is no generally accepted framework on how to assess or predict variant pathogenicity.

After years in making, I am glad to be able to share our attempt on establishing a framework for combined functional and computational assessment of variant pathogenicity in the sodium leak channel NALCN:
www.biorxiv.org/content/10.1...

Wonderful visit to beautiful Bergen, Norway. Big thanks to @herculeria.bsky.social for hosting and to Tim Lynagh for guiding me up the local hills

“It’s the company that matters!”

This is certainly true for acid-sensing ion channel 1a, whose function is modulated by the presence of monocarboxylate transporter 1

All was made possible by the drive & curiosity of the fantastic @mette-h-poulsen.bsky.social

www.biorxiv.org/cgi/content/...

Our latest paper on the sodium leak channel NALCN complex is now online. We found that the neuronal SNARE proteins syntaxin 1A and SNAP25 inhibit sodium leak currents both in heterologous systems and in neurons!

www.science.org/doi/10.1126/...

...and outlines how mutations in the pre-M1 / re-entrant loop can shift the conformational equilibrium between closed and open states.

Using a combination of structures, ephys and VCF, we demonstrate that the mechanism of channel activation by protons differs from that by peptide toxins...

Grateful for having contributed to this work by the Isabelle Baconguis group, who solved eleven (!) new structures of hASIC1a to show that open states require linear transmembrane helices, while desensitized states display a dazzling structural diversity
www.biorxiv.org/content/10.1...
#ionchannels

First post here: just returned from an inspiring trip to meet colleagues and collaborators at Genentech, UC Davis and UW Seattle - big thanks to the wonderful hosts!